Several plants of the Tylophora genus have been used medicinally as anti-inflammatory, antiarthritis, and anti-amoebic agents in East Asian countries (Jiangsu New Medical College. Dictionary of Chinese Traditional Medicine; Shanghai: Shanghai Science and Technology Publishing House, 1977; pp 1747; Baumgartner, B. et al., Phytochemistry 1990, 29, 33327-33330; Wu, P. L. et al., Heterocycles 2002, 57, 2401). In addition to various traditional therapeutic uses, tylophorine, the biologically active constituent, has been the target of synthetic modification for many years because of its profound cytotoxicity (Gellert, E.; Rudzats, R. J. Med. Chem. 1964; 7:361-362; Rao, K. V. et al., J. Pharm. Sci 1971; 60:1725-1726; Suffness, M.; Cordell, G. A. In The Alkaloids, Chemistry and Pharmacology, Brossi, A., Ed.; Academic Press: New York, 1985; Vol. 25, pp 3-355; Tanner, U.; Wiegrebe, W., Arch. Pharm. (Weinheim) 1993; 326:67-72). Tylophorine (1) (Chart 1) and its phenanthroindolizidine alkaloid analog (also referred to as tylophora alkaloids), have been isolated primarily from plants of the family Asclepiadaceae, including members of the genuses Tylophora, Vincetoxicum, Pergularia, Cynanchum (Gellert, E. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W. Ed.; Academic Press: New York, 1987; pp 55-132; Gellert, E. The indolizidine alkaloids. J. Nat. Prod. 1982; 45:50-73; Govindachari, T. R. In The Alkaloids, Chemistry and Pharmacology, Manske, R. H. F. Ed.; Academic Press: New York, 1976; Vol. 9, 517-528; Bick, I. R. C.; Sinchai, W. In The Alkaloids, Chemistry and Pharmacology, Manske, R. H. F., Rodrigo, R. G. A, Eds.; Academic Press: New York, 1981; Vol 19, pp 193-220).

The clinical use of chemotherapeutic agents against malignant tumors is successful in many cases, but suffers from major drawbacks. One drawback is lack of selectivity, which leads to severe systemic side effects and limited efficacy. Another major problem is the emergence/selection of drug-resistance.
The drug development failure of tylocrebrine (2) (Chart 1), a positional isomer of tylophorine, in 1966 was due to a central nervous system toxicity, manifested by ataxia and disorientation. This disappointing clinical result discouraged further consideration of these alkaloids for drug development. However, in the 1990s, tylophorine analogs deemed previously not to warrant further research were re-screened for antitumor potential by the National Cancer Institute (NCI) using a 60-tumor cell line panel. These compounds showed potent and uniform activity against 54 human tumor cell lines with mean GI50<10−10 M. Moreover, tylophorine F (3) and tylophorine G (4) were quite active toward refractory cancer cell lines including melanoma and lung cancer.
Recent studies (Gao, W. et al., Cancer Res. 2004; 64:678-688; Stærk, D. et al., J. Nat. Prod. 2002, 65, 1299-1302) have shown that tylophorine analogs exhibit potent cytotoxic activity against a broad range of human cancer cells and sublines resistant or cross-resistant to various conventional anticancer drugs, such as etoposide (VP-16), taxol, topotecan, adriamycin, cytosine arabinoside, gemcitabine, hydroxyurea, or camptothecin (CPT). Gao et al also found that NSC-717335 (5), a stereoisomer of tylophorine, significantly inhibits activator protein-1, CRE, and nuclear factor KB (NF-κB) mediated transcription. NF-κB has been suggested to be a mechanism of drug resistance because of its antiapoptotic role (Wang, C. Y. et al., Nat. Med. 1999, 5, 412-417). Other research implicates NF-κB in the regulation of p-glycoprotein, a well known mechanism of multidrug resistance to chemotherapy.